The proposed experiments have been designed to determine the anatomical and functional connections among specific neurons in the brainstem and spinal cord that are involved in modulating nociception. The neuronal cell groups to be examined include the nucleus raphe magnus, nucleus reticularis gigantocellularis pars a, periaqueductal gray, pedunculopontine tegmental nucleus, A5 and A7 catecholamine cell groups, and an enkephalin cell group in the dorsolateral pontine tegmentum that innervates the spinal cord dorsal horn. Neurons in these cell groups are neurochemically diverse and contain neurotransmitters such as serotonin, norepinephrine, acetylcholine, enkephalins, neurotensin, substance P, excitatory amino acids, and probably many other unidentified peptides and amino acids. These experiments will determine the neurotransmitters contained in these neurons, the anatomical connections among these immunochemically-identified neurons, including the axonal trajectories, and the location of synaptic contacts made by these neurons. Functional neuronal connections will be determined by activating selected neurons using electrical or chemical stimulation and determining the resulting effects on nociception and electrophysiological recordings of postsynaptic neurons. Pharmacological analysis using selective neurotransmitter agonists and antagonists will be used to provide evidence for the function of specific neurons in nociceptive modulation. These anatomical, electrophysiological, and pharmacological experiments are designed to provide converging evidence that will be used to identify and define specific neuronal circuits in the brainstem and spinal cord that modulate nociception. Understanding the neural circuits that regulate nociception could lead to new and effective treatments for the numerous pain states that are refractory to current therapeutic methods. In addition, understanding the pharmacology of pain modulatory circuits may provide insights into new drug treatments for pain states that are currently treated with opioid drugs. Thus, non-opioid drugs may be developed that lack the unfortunate and dangerous side effects of the opioid analgesic agents.